EP0325571B1 - New amines, their use and preparation - Google Patents
New amines, their use and preparation Download PDFInfo
- Publication number
- EP0325571B1 EP0325571B1 EP89850017A EP89850017A EP0325571B1 EP 0325571 B1 EP0325571 B1 EP 0325571B1 EP 89850017 A EP89850017 A EP 89850017A EP 89850017 A EP89850017 A EP 89850017A EP 0325571 B1 EP0325571 B1 EP 0325571B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydroxy
- methyl
- phenylpropylamine
- yield
- tert
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001412 amines Chemical class 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 51
- KISZTEOELCMZPY-UHFFFAOYSA-N 3,3-diphenylpropylamine Chemical class C=1C=CC=CC=1C(CCN)C1=CC=CC=C1 KISZTEOELCMZPY-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 methoxy, hydroxy, carbamoyl Chemical group 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 12
- 150000007513 acids Chemical class 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000003287 optical effect Effects 0.000 claims abstract description 6
- 239000000812 cholinergic antagonist Substances 0.000 claims abstract description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000001302 tertiary amino group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims abstract 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- IDCXQMVSIIJUEH-UHFFFAOYSA-N 3,3-diphenylpropan-1-ol Chemical compound C=1C=CC=CC=1C(CCO)C1=CC=CC=C1 IDCXQMVSIIJUEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- LVZFXRLTAJXZEI-UHFFFAOYSA-N 1-[3-(2-methoxyphenyl)-3-phenylpropyl]-2,2,6,6-tetramethylpiperidine Chemical compound COC1=CC=CC=C1C(C=1C=CC=CC=1)CCN1C(C)(C)CCCC1(C)C LVZFXRLTAJXZEI-UHFFFAOYSA-N 0.000 claims description 5
- OOGJQPCLVADCPB-UHFFFAOYSA-N 2-[3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound C=1C(C)=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 OOGJQPCLVADCPB-UHFFFAOYSA-N 0.000 claims description 4
- LXCSXXCUJFGCER-UHFFFAOYSA-N 2-[3-[di(propan-2-yl)amino]-1-(2-hydroxyphenyl)propyl]phenol Chemical compound C=1C=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1O LXCSXXCUJFGCER-UHFFFAOYSA-N 0.000 claims description 3
- UKUSJSXFVBREPW-UHFFFAOYSA-N 2-[3-[di(propan-2-yl)amino]-1-phenylpropyl]benzene-1,4-diol Chemical compound C=1C(O)=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UKUSJSXFVBREPW-UHFFFAOYSA-N 0.000 claims description 3
- YEEOXEKIQFQHFC-UHFFFAOYSA-N 2-[3-[tert-butyl(methyl)amino]-1-phenylpropyl]phenol Chemical compound C=1C=CC=C(O)C=1C(CCN(C)C(C)(C)C)C1=CC=CC=C1 YEEOXEKIQFQHFC-UHFFFAOYSA-N 0.000 claims description 3
- DYMSJANEHGEKSI-UHFFFAOYSA-N 3,3-diphenylpropanamide Chemical compound C=1C=CC=CC=1C(CC(=O)N)C1=CC=CC=C1 DYMSJANEHGEKSI-UHFFFAOYSA-N 0.000 claims description 3
- XNSHFBLQVWIYMW-UHFFFAOYSA-N 3-(2-methoxyphenyl)-3-phenyl-n,n-di(propan-2-yl)propan-1-amine Chemical compound COC1=CC=CC=C1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 XNSHFBLQVWIYMW-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000001035 methylating effect Effects 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 230000000063 preceeding effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 91
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 41
- 239000012458 free base Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 40
- 239000003921 oil Substances 0.000 description 39
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 17
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- 239000000126 substance Substances 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 11
- 150000003335 secondary amines Chemical class 0.000 description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 150000002596 lactones Chemical class 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- GWJFXNIOZDWELF-UHFFFAOYSA-N 4-[4-phenyl-4-(2-phenylmethoxyphenyl)butyl]benzenesulfonic acid Chemical compound C1=CC=C(C=C1)COC2=CC=CC=C2C(CCCC3=CC=C(C=C3)S(=O)(=O)O)C4=CC=CC=C4 GWJFXNIOZDWELF-UHFFFAOYSA-N 0.000 description 7
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 7
- 229960004484 carbachol Drugs 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229960002748 norepinephrine Drugs 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 5
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 5
- CKZBVFSHTBANKT-UHFFFAOYSA-N 4-[4,4-bis(2-methoxy-5-methylphenyl)butyl]benzenesulfonic acid Chemical compound CC1=CC(=C(C=C1)OC)C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=C(C=CC(=C3)C)OC CKZBVFSHTBANKT-UHFFFAOYSA-N 0.000 description 5
- RDPSSLMVXZVIRH-UHFFFAOYSA-N 4-[4-(2-methoxy-5-methylphenyl)-4-phenylbutyl]benzenesulfonic acid Chemical compound CC1=CC(=C(C=C1)OC)C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=CC=CC=C3 RDPSSLMVXZVIRH-UHFFFAOYSA-N 0.000 description 5
- VIEFLKNEIZHVNQ-UHFFFAOYSA-N 4-[4-(2-methoxyphenyl)-4-phenylbutyl]benzenesulfonic acid Chemical compound COC1=CC=CC=C1C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=CC=CC=C3 VIEFLKNEIZHVNQ-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 230000001078 anti-cholinergic effect Effects 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 230000008602 contraction Effects 0.000 description 5
- 239000010779 crude oil Substances 0.000 description 5
- 229940043279 diisopropylamine Drugs 0.000 description 5
- RJWLXGOSIRVRAR-UHFFFAOYSA-N dimethylresorcinol Natural products CC1=CC=C(O)C(C)=C1O RJWLXGOSIRVRAR-UHFFFAOYSA-N 0.000 description 5
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 5
- IKGDNKGEBZMQRE-UHFFFAOYSA-N methyl 3,3-bis(2-methoxy-5-methylphenyl)propanoate Chemical compound C=1C(C)=CC=C(OC)C=1C(CC(=O)OC)C1=CC(C)=CC=C1OC IKGDNKGEBZMQRE-UHFFFAOYSA-N 0.000 description 5
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 210000003932 urinary bladder Anatomy 0.000 description 5
- PWACUFGLHIZTET-UHFFFAOYSA-N 3,3-bis(2-methoxyphenyl)propyl 4-methylbenzenesulfonate Chemical compound COC1=CC=CC=C1C(C=1C(=CC=CC=1)OC)CCOS(=O)(=O)C1=CC=C(C)C=C1 PWACUFGLHIZTET-UHFFFAOYSA-N 0.000 description 4
- FVSKBYPMPFPPKI-UHFFFAOYSA-N 4-[4,4-bis(2,4-dimethoxyphenyl)butyl]benzenesulfonic acid Chemical compound COC1=CC(=C(C=C1)C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=C(C=C(C=C3)OC)OC)OC FVSKBYPMPFPPKI-UHFFFAOYSA-N 0.000 description 4
- ZFZJPRQTWXCQAO-UHFFFAOYSA-N 4-[4,4-bis(4-methyl-2-phenylmethoxyphenyl)butyl]benzenesulfonic acid Chemical compound CC1=CC(=C(C=C1)C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=C(C=C(C=C3)C)OCC4=CC=CC=C4)OCC5=CC=CC=C5 ZFZJPRQTWXCQAO-UHFFFAOYSA-N 0.000 description 4
- JVEKBXOKCQEDDB-UHFFFAOYSA-N 4-[4-(2,4-dimethoxyphenyl)-4-phenylbutyl]benzenesulfonic acid Chemical compound COC1=CC(=C(C=C1)C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=CC=CC=C3)OC JVEKBXOKCQEDDB-UHFFFAOYSA-N 0.000 description 4
- ZHOJTDYUNSZYDM-UHFFFAOYSA-N 4-[4-(2-methoxy-4-methylphenyl)-4-phenylbutyl]benzenesulfonic acid Chemical compound CC1=CC(=C(C=C1)C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=CC=CC=C3)OC ZHOJTDYUNSZYDM-UHFFFAOYSA-N 0.000 description 4
- DWLWUQNMABLELT-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-4-(2-methoxyphenyl)butyl]benzenesulfonic acid Chemical compound COC1=CC=CC=C1C(CCCC2=CC=C(C=C2)S(=O)(=O)O)C3=CC=C(C=C3)F DWLWUQNMABLELT-UHFFFAOYSA-N 0.000 description 4
- SCIKJKAJUJZPDC-UHFFFAOYSA-N 4-[4-[2,3-bis(phenylmethoxy)phenyl]-4-phenylbutyl]benzenesulfonic acid Chemical compound C1=CC=C(C=C1)COC2=CC=CC(=C2OCC3=CC=CC=C3)C(CCCC4=CC=C(C=C4)S(=O)(=O)O)C5=CC=CC=C5 SCIKJKAJUJZPDC-UHFFFAOYSA-N 0.000 description 4
- DUYOZOWPJSUGLZ-UHFFFAOYSA-N 4-[4-[2,5-bis(phenylmethoxy)phenyl]-4-phenylbutyl]benzenesulfonic acid Chemical compound C1=CC=C(C=C1)COC2=CC(=C(C=C2)OCC3=CC=CC=C3)C(CCCC4=CC=C(C=C4)S(=O)(=O)O)C5=CC=CC=C5 DUYOZOWPJSUGLZ-UHFFFAOYSA-N 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 4
- 229940073608 benzyl chloride Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 150000002440 hydroxy compounds Chemical class 0.000 description 4
- 210000003405 ileum Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- NAXBIQYAUFIGEO-UHFFFAOYSA-N methyl 3,3-bis(4-methyl-2-phenylmethoxyphenyl)propanoate Chemical compound C=1C=C(C)C=C(OCC=2C=CC=CC=2)C=1C(CC(=O)OC)C1=CC=C(C)C=C1OCC1=CC=CC=C1 NAXBIQYAUFIGEO-UHFFFAOYSA-N 0.000 description 4
- GOJQENSDXKCFBE-UHFFFAOYSA-N methyl 3-(2-methoxy-4-methylphenyl)-3-phenylpropanoate Chemical compound C=1C=C(C)C=C(OC)C=1C(CC(=O)OC)C1=CC=CC=C1 GOJQENSDXKCFBE-UHFFFAOYSA-N 0.000 description 4
- GSSZTVPIIXQZQF-UHFFFAOYSA-N methyl 3-[2,5-bis(phenylmethoxy)phenyl]-3-phenylpropanoate Chemical compound C=1C(OCC=2C=CC=CC=2)=CC=C(OCC=2C=CC=CC=2)C=1C(CC(=O)OC)C1=CC=CC=C1 GSSZTVPIIXQZQF-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 4
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 4
- 210000003240 portal vein Anatomy 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- IEKNHKFBHBENMC-UHFFFAOYSA-N 2-[3-[di(propan-2-yl)amino]-1-phenylpropyl]phenol Chemical compound C=1C=CC=C(O)C=1C(CCN(C(C)C)C(C)C)C1=CC=CC=C1 IEKNHKFBHBENMC-UHFFFAOYSA-N 0.000 description 3
- WUZOSCQDCUXAMB-UHFFFAOYSA-N 3,3-bis(2,4-dimethoxyphenyl)-n,n-di(propan-2-yl)propan-1-amine Chemical compound COC1=CC(OC)=CC=C1C(CCN(C(C)C)C(C)C)C1=CC=C(OC)C=C1OC WUZOSCQDCUXAMB-UHFFFAOYSA-N 0.000 description 3
- KCQULGJHQFFMET-UHFFFAOYSA-N 3,3-bis(4-methyl-2-phenylmethoxyphenyl)-n,n-di(propan-2-yl)propan-1-amine Chemical compound C=1C=C(C)C=C(OCC=2C=CC=CC=2)C=1C(CCN(C(C)C)C(C)C)C1=CC=C(C)C=C1OCC1=CC=CC=C1 KCQULGJHQFFMET-UHFFFAOYSA-N 0.000 description 3
- BZQGAPWJKAYCHR-UHFFFAOYSA-N 3,3-diphenylpropanoic acid Chemical class C=1C=CC=CC=1C(CC(=O)O)C1=CC=CC=C1 BZQGAPWJKAYCHR-UHFFFAOYSA-N 0.000 description 3
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- BJQJPTJDNINOMT-UHFFFAOYSA-N methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropanoate Chemical compound C=1C(C)=CC=C(OC)C=1C(CC(=O)OC)C1=CC=CC=C1 BJQJPTJDNINOMT-UHFFFAOYSA-N 0.000 description 1
- FCMNDLLGEGVMQQ-UHFFFAOYSA-N methyl 3-(2-methoxyphenyl)prop-2-enoate Chemical compound COC(=O)C=CC1=CC=CC=C1OC FCMNDLLGEGVMQQ-UHFFFAOYSA-N 0.000 description 1
- MOIPEYDSFDQICQ-UHFFFAOYSA-N methyl 3-(4-hydroxyphenyl)-3-(2-methoxyphenyl)propanoate Chemical compound C=1C=CC=C(OC)C=1C(CC(=O)OC)C1=CC=C(O)C=C1 MOIPEYDSFDQICQ-UHFFFAOYSA-N 0.000 description 1
- CQBOBUVAAKSYDB-UHFFFAOYSA-N methyl 3-(5-chloro-2-methoxyphenyl)-3-phenylpropanoate Chemical compound C=1C(Cl)=CC=C(OC)C=1C(CC(=O)OC)C1=CC=CC=C1 CQBOBUVAAKSYDB-UHFFFAOYSA-N 0.000 description 1
- YXKAZTAUZGFXHK-UHFFFAOYSA-N methyl 3-[2,3-bis(phenylmethoxy)phenyl]-3-phenylpropanoate Chemical compound C=1C=CC(OCC=2C=CC=CC=2)=C(OCC=2C=CC=CC=2)C=1C(CC(=O)OC)C1=CC=CC=C1 YXKAZTAUZGFXHK-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000001114 myogenic effect Effects 0.000 description 1
- RIRUQRWTLSKQCL-UHFFFAOYSA-N n-[3,3-bis(2-methoxy-5-methylphenyl)propyl]-2-methylbutan-2-amine Chemical compound C=1C(C)=CC=C(OC)C=1C(CCNC(C)(C)CC)C1=CC(C)=CC=C1OC RIRUQRWTLSKQCL-UHFFFAOYSA-N 0.000 description 1
- ATZRJHDCUGVLRF-UHFFFAOYSA-N n-[3-(2-methoxy-5-methylphenyl)-3-phenylpropyl]-2-methylbutan-2-amine Chemical compound C=1C(C)=CC=C(OC)C=1C(CCNC(C)(C)CC)C1=CC=CC=C1 ATZRJHDCUGVLRF-UHFFFAOYSA-N 0.000 description 1
- ZFXDDOCLHRYOQL-UHFFFAOYSA-N n-[3-(2-methoxy-5-methylphenyl)-3-phenylpropyl]-n,2-dimethylbutan-2-amine Chemical compound C=1C(C)=CC=C(OC)C=1C(CCN(C)C(C)(C)CC)C1=CC=CC=C1 ZFXDDOCLHRYOQL-UHFFFAOYSA-N 0.000 description 1
- YHTQEOOIWYAVBQ-UHFFFAOYSA-N n-[3-phenyl-3-(2-phenylmethoxyphenyl)propyl]adamantan-1-amine Chemical compound C1C(C2)CC(C3)CC2CC13NCCC(C=1C(=CC=CC=1)OCC=1C=CC=CC=1)C1=CC=CC=C1 YHTQEOOIWYAVBQ-UHFFFAOYSA-N 0.000 description 1
- PSYZSLNPXWOUIM-UHFFFAOYSA-N n-methyl-n-[3-phenyl-3-(2-phenylmethoxyphenyl)propyl]adamantan-1-amine Chemical compound C1C(C2)CC(C3)CC2CC13N(C)CCC(C=1C(=CC=CC=1)OCC=1C=CC=CC=1)C1=CC=CC=C1 PSYZSLNPXWOUIM-UHFFFAOYSA-N 0.000 description 1
- RPVBCVQKDPOMII-UHFFFAOYSA-N n-tert-butylethanimine Chemical compound CC=NC(C)(C)C RPVBCVQKDPOMII-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000948 sympatholitic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 239000011579 vitamin B4 Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Definitions
- the present invention relates to novel 3,3-diphenylpropylamino derivatives, to pharmaceutical compositions containing the same, and to the use of said derivatives for preparing drugs.
- Swedish patent No. 215499 discloses certain 3,3-diphenylpropylyamines having an advantageous effect on the heart and circulation. These pharmacologically active 3,3-diphenylpropylamines are secondary amines. Said Swedish patent also discloses certain chemical intermediates which are tertiary amines carrying aromatic substituents on the amine nitrogen. Neither the end products (secondary amines) nor the intermediates (tertiary amines) have any hydroxy or methoxy groups as substituents in the ortho positions of the phenyl rings, but only meta and para substituents are specifically disclosed.
- this drug has anti-cholinergic properties, and is well resorbed in the body.
- this drug has a very long biological half-life and it is a multi-effect drug also having other pharmacological properties such as Ca-antagonist, noradrenaline antagonist and anti-histamine properties as well as a pronounced effect on the heart.
- US-A-3.446.901, GB-A-1.169.944 and GB-A-1.169.945 disclose certain 3,3-diphenylpropylamine derivatives and pharmaceutical compositions having antidepressant activity, i.a. N,N-dimethyl-3-(2-methoxyphenyl)-3-phenylpropylamine, which is considered to be the closest prior art as regards chemical structure (see also the comparative tests reported at the end of this specification).
- DK-A-111.894 discloses a special process for preparing certain diphenylalkylamines having an effect on the heart and circulation. The specifically described compounds are primary or secondary amines, and none of them has any hydroxy or alkoxy substituent in ortho position of the phenyl rings.
- R I signifies hydrogen or methyl
- R 2 , R 3 and R 4 independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphanoyl or halogen
- X represents a tertiary amino group of formula 11 wherein R 5 and R 6 signify non-aromatic hydrocarbol groups, which may be the same or different and which together contain at least three carbon atoms, preferably at least four carbon atoms, especially at least five carbon atoms, and wherein R 5 and R 6 may form a ring together with the amine nitrogen, said ring preferably having no other hetero atom than the amine nitrogen.
- the compounds of formula I can form salts with physiologically acceptable acids, organic and inorganic, and the invention comprises the free bases as well as the salts thereof.
- acid addition salts include the hydrochloride, hydrobromide, hydrogen fumarate, and the like.
- the invention comprises the racemic mixture as well as the individual enantiomers as such.
- a preferred sub-class of compounds according to the invention comprises tertiary amines offormula I, wherein each of R 5 and R 6 independently signifies C 1-8 -alkyl, especially C 1-6 -alkyl, or adamantyl, R 5 and R 6 together comprising at least three, preferably at least four carbon atoms.
- R 5 and R 6 may carry one or more hydroxy groups, and they may be joined to form a ring together with the amine nitrogen atom.
- Presently preferred tertiary amino-groups X in formula I include the following groups a)-f), each of which may carry one or more hydroxy groups.
- hydroxy protecting groups according to i) above can e.g. be done by treatment with hydrobromic acid, borontribromide or by catalytic hydrogenation.
- the separation of mixtures of optical isomers, according to ii) above, into the individual enantiomers can e.g. be achieved by fractional crystallization of salts with chiral acids or by chromatographic separation on chiral columns.
- Novel compounds of formula VIII wherein R'-R 4 are as defined above, and the corresponding protected compounds (e.g. comprising protected hydroxy groups), are useful as chemical intermediates for the preparation of e.g. the compounds of formula I, and they can be prepared by means of several different methods which are known per se, such as by addition of ethylene oxide (X) to a correspondingly substituted diphenylmethane (IX) in the presence of a suitable base such as sodium amide :
- the compounds VIII can also be prepared by reduction of the corresponding 3,3-diphenylpropionic acids, preferably using complex metal hydrides.
- the 3,3-diphenylpropanols VIII can conveniently be converted into the corresponding reactively esterified derivatives III in a manner known per se by displacing the hydroxy groups with e.g. a halogen atom or an alkyl or arylsulphonyloxy group.
- the 3,3-diphenylamides offormula V used as starting materials in method b), can e.g. be prepared by reacting the above mentioned 3,3-diphenyipropionic acids with an appropriate amine.
- the secondary amines used as starting materials in method c) can conveniently be prepared by reacting a primary amine H 2 N-Z (wherein Z is as defined above) with a corresponding reactively esterified 3,3-diphenylpropanol in analogy with method a) above, or by reduction of the corresponding secondary 3,3-diphenyl- propionamides in analogy with method b) above.
- the secondary amines can also be prepared by reduction of unsaturated hydroxyamines XI
- R 1 -R 4 and Z are as defined above, either in one step by catalytic hydrogenation, or by reduction to the corresponding saturated hydroxyamine, preferably using a complex metal hydride such as lithium aluminium hydride, followed by removal of the hydroxy group by catalytic reduction.
- the hydroxy group may first be split off as water, followed by reduction of the formed unsaturated amine.
- the unsaturated hydroxy amines XI can conveniently be prepared by the addition of a Schiff base of formula XII wherein Z is as defined above,
- starting materials Vlla, Vllb for process d) can be prepared by methods known per se, such as by addition of an organometallic compound XIVa or XIVb to a ketoamine XVa or XVb respectively to form a corresponding hydroxy amine XVI and, if desired, splitting off water from compound XVI.
- the compounds of formula 1, in the form of free bases or salts with physiologically acceptable acids can be brought into suitable galenic forms, such as compositions for oral use, for injection, orthe like, in accordance with accepted pharmaceutical procedures.
- suitable galenic forms such as compositions for oral use, for injection, orthe like, in accordance with accepted pharmaceutical procedures.
- Such pharmaceutical compositions according to the invention comprise the compounds of formula I in association with compatible pharmaceutically acceptable carrier materials, or diluents, as is well known in the art.
- the carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous or parenteral administration such as : water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
- Such compositions may also contain other pharmaceutically active agents, and conventional additives such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers,
- compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, capsules, powders, syrups, elixirs and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, and the like.
- the compounds and compositions according to the invention can be used for treating cholin-mediated disorders such as urinary incontinence.
- the dosage depends on several factors such as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, the severity of the condition to be treated, and the like.
- the daily dosage may, for example, be from about 0.05 mg to about 4 mg per kilo of body weight, administered in one or more doses, e.g. containing from about 0.05 to about 200 mg each.
- Solvents are abbreviated as follows :
- Amines are abbreviated as follows :
- Methyl 3,3-bis-(2,4-dimethoxyphenyl)propionate (XV) was obtained in a similar way from methyl 2,4-dimethoxycinnamate and dimethyl resorcinol.
- the product thus obtained contained about 23% of dimethyl resorcinol. It was taken to the next step without further purification.
- a Grignard reagent was prepared in the usual manner from o-bromoanisole (93.5 g, 0.5 mol) and magnesium (12 g, 0.5 mol) in 100 ml dry ether.
- a solution of p-fluorobenzaldehyde (62 g, 0.5 mol) in 100 ml ether was added dropwise to this solution. After about 1 h, the mixture was decomposed with NH 4 CI and worked up, giving 100.6 g (87%) of 4-fluoro-2'-methoxy-diphenylmethanol. Recrystallization from IPE-PETgave white crystals, m.p. 88°.
- the free base was obtained in 86% yield from the tosylate (XLVIII) of Example 41) and was converted to the fumaric acid salt in the usual way. M.p. 134-136° (acetone-IPE) or 163-164° (methanol).
- This compound was similarly prepared from the tosylate (XXIX) of Example 4d) and 2-amino-2-methylpropanol.
- the solid product was crystallized from diisopropyl ether and melted at 103°C. It was used as start material in Example 7p).
- This compound was similarly prepared from the tosylate (XXIX) of Example 4d) and 1-aminoadamantane. It was used as start material in Example 7q).
- the hydrochloridesemihydrate was prepared in acetonitrile and melted at 225°C.
- Example 4a The tosylate (XXVII) of Example 4a) was heated with a large excess of tert.butylamine as described in Example 5, giving the free base in 78% yield, which was converted to the oxalic acid salt in the usual manner. M.p. 135-136° (acetone-ether).
- the free base was obtained as above in 78% yield from the tosylate (XXVIII) of Example 4c).
- the HCI salt had m.p. 184-185° (acetone-methanol-IPE).
- the free base was obtained in 84% yield from the tosylate (XXIX) of Example 4d).
- the oxalic acid salt had m.p. 198° (acetone-ether).
- the free base was obtained in quantitative yield from the tosylate (XXXI) of Example 4b).
- the HCI-salt had m.p. 138-149° (methanol-isopropanol). It was associated with 3/4 mol of water.
- the free base was obtained in 85% yield from the tosylate (XXXIII) of Example 4g).
- the HCI salt had m.p. 188° (ethanol-ether).
- the free base was obtained in 94% yield from the tosylate (XXXIV) of Example 4h).
- the HCL-salt had m.p. 210° (acetone-ether).
- the free base was obtained in 88% yield from the tosylate (XLVIII) of Example 41).
- the HCI-salt had m.p. 205°.
- the free base was obtained in 95% yield from the tosylate (XXX) of Example 4e) and tert. amylamine.
- the HCI-salt had m.p. 188-189° (ethanol-acetone).
- the free base was obtained in 96% yield from the amine (L) of Example 6a).
- the HCI-salt had m.p. 187-190° (acetone-ether).
- the free base was obtained in 96% yield from the amine (LIX) of Example 6j).
- the HCI-salt had m.p. 180-190° and seems to be associated with 1/4 mol of water.
- the HCI-salt had m.p. 203-204° (acetone-ether) and seems to be associated with 1/4 mol of water.
- the above secondary amine as the free base, was methylated with formaldehydeformic acid as described in Example 7, giving the tertiary amine in 96% yield.
- the fumaric acid salt had m.p. 185-190° (acetone).
- Example 5 0 The benzyloxy compound from Example 5 0 was hydrogenolysed as described in Example 9q).
- the free base was converted to the hydrochloride semihydrate which was crystallized from acetone.
- the compound melts with decomposition at about 150°C.
- Example 9q The benzyloxy compound from Example 7p was hydrogenolysed as described in Example 9q).
- Example 9q The benzyloxy compound from Example 7q was hydrogenolysed as described in Example 9q).
- the free hydroxyamine was obtained as a glassy mass. It was dissolved in anhydrous ether and treated with an excess of hydrogen chloride in ether. The hydrochloride precipitated as a powder which decomposed at about 220°C.
- the solid product consisting of N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropionamide is filtered off, dried and added in small portions to a stirred suspension of lithium aluminium hydride (6.0 g, 0.16 mol) in dry ether (700 ml). The mixture is refluxed for 2 days. Excess of hydride is destroyed by the careful addition of water, the ether layer is separated and dried with anhydrous sodium sulfate. After filtration the solution is added to a solution of excess fumaric acid in ether. The precipitated salt is collected and crystallized from 2-propanol. The hydrogen fumarate melts at 176°C.
- N,N-Diisopropyl-3-(5-chloro-2-hydroxyphenyl)-3-phenylpropylamine is similarly prepared.
- the hydrochloride melts at 202-3°C.
- (+)-N,N-Diisopropyl-3-(2-hydroxyphenyl)-3-phenylpropylamine (31.1 g, 0.10 mol) is dissolved in 300 ml of ethanol.
- a solution of L(+)-tartaric acid (15.0 g, 0.10 mol) in 400 ml of ethanol is added.
- the mixture is heated a few minutes in a boiling water bath and seeded with crystals obtained by cooling and scratching a small sample of the main solution.
- the mixture is chilled at about 4°C over-night whereupon the crystalline precipitate is filtered off, washed with cold ethanol and recrystallized repeatedly from ethanol.
- (+)-N,N-Diisopropyl-3-(2-hydroxyphenyl)-3-phenylpropylamine is similarly prepared using D-(-)-tartaric acid.
- the hydrogen-D-(-)tartrate has [ ⁇ ] +10.0°.
- the free amine has [ ⁇ ] +5.6°, both measured as 5% solutions in methanol.
- Example 15 (continuation of Example 3)
- Example 16 (continuation of Example 4)
- Example 17 (continuation of Example 5)
- N,N-Diisopropyl-3-(2-methoxyphenyl)-3-(2-methoxy-5-methylphenyl)propylamine was obtained in the same way in 49% crude yield from the tosylate CXV of Example 16n).
- the product (oil) had a purity of 100% according to GC.
- Example 18 (continuation of Example 6)
- Example 19 (continuation of Example 7)
- CXIX N-Methyl-N-tert.butyl-3-(5-chloro-2-methoxyphenyl)-3-(2-methoxyphenyl)propylamine
- N-Methyl-N-tert.butyl-3-(2-methoxyphenyl)-3-(2-methoxy-5-methylphenyl)propylamine was prepared in a similar way in 98% yield from the amine CXVIII of Example 18q).
- the free base (oil) had a purity of 96% by GC.
- Example 20 (continuation of Example 9)
- CXXIV N-Methyl-N-tert.butyl-3-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyphenyl)propylamine
- Example 21 (continuation of Example 10)
- N,N-Diisopropyl-3-(2-methoxyphenyl)-3-phenylpropionamide was obtained as o pale yellow oil in quantitative yield from 3-(2-methoxyphenyl)-3-phenylpropionic acid in the manner described for the amide of Example 10a).
- This amide (27 g, 0.08 mol) in toluene (50 g) was added dropwise under r.t. to a 3.4 M toluenic solution of SMEAH (50 g, 0,17 mol) diluted with an equal weight of toluene. The mixture was stirred at 60-70° for 2 h, cooled, treated with excess od 2N NaOH.
- the bladder strips were immediately mounted vertically in 5 ml organ baths containing Na +- Krebs solution aerated with carbogene gas to maintain the pH at about 7.4.
- the temperature, 37°C was thermostatically controlled by a Lauda MS3 thermostatic circulator.
- the preparations were suspended between two hooks, one of which was connected to a Grass Instruments FT03 force transducer.
- the isomeric tension of the preparations was recorded by a Grass polygraph model 79D.
- the resting tension was applied to approximately 5 mN.
- the strips were allowed to stabilize for at least 45 minutes. During this period the resting tension was adjusted to 5 mN and the preparations were repeatedly washed.
- each antagonist was tested in a concentration of 10-t1M, on. two bladder-strips from different guinea-pigs.
- a reproducible response with 3 ⁇ 10 -6 M carbachol was obtained, the strips were incubated with the antagonist for 15 minutes before the next carbachol was added. If the antagonist produced more than 50% inhibition of the response to carbachol, a complete concentration-inhibition curve was also made. In the complete inhibition curves, the strips were then incubated for 60 minutes with a fixed concentration of the antagonist before the next addition of carbachol. The effect of the antagonists was calculated as per cent inhibition of the mean of the initial agonist-induced contractions. To generate concentration-inhibition curves the antagonists were studied in 6-8 concentrations and for each concentration a fresh preparation was used, i.e. the strips were only exposed to the antagonist once before they were discarded.
- the rat is killed by a blow on the neck and decapitated.
- the abdomen is opened, the vein is dissected free from fat, cut open longitudinally and mounted in an organ bath. Changes in isometric tension is registered by a force displacement transducer, connected to an amplifier and a writing oscillograph.
- the chosen doses give about 70% of maximal response.
- the agonist is added to the bath at 10-minutes intervals. When reproducible contractions are obtained a fixed concentration of the test substance is added to the bath. After an incubation period of 10 minutes noradrenaline is added. The next concentration of the test substance is added when the original response of the agonist is obtained.
- the antagonistic effect of the substance is calculated as per cent inhibition of the mean response by three preceding doses of the agonist.
- the guinea pig is killed by a blow on the neck and decapitated.
- the abdomen is opened and about 2 cm of the ileum is cut off about 15 cm above the ileocaecal junction.
- the piece of ileum is washed with buffer and mounted in an organ bath. Changes in isometric tension is recorded by a force displacement transducer, connected to an amplifier and a writing oscillograph.
- the chosen dose of histamine gives about 70% of maximal response.
- the agonist is added to the bath at 3-minutes intervals. When reproducible contractions are obtained a fixed concentration of the test substance is added to the bath. After an incubation period of 2-10 minutes a new contraction is induced by histamine. The next concentration of the test substance is added when the original response of the agonist is obtained.
- the agonistic effect of the test substance is calculated as per cent inhibition of the mean response by three preceding doses of histamine.
- the antagonists to be tested were dissolved in 0.9% NaCI. If they were not soluble in 0.9% NaCI they were dissolved in double distilled water. The solutions were prepared on the day of the experiment.
- mice 25 g were placed in a mouse holder.
- the tested compounds were given as i.v. bolus doses in one of the four tail-veins, with a volume of 0.01 ml/g mouse.
- Each substance concentration was given to a group of four mice. 4-5 different concentrations of the antagonists were made and tested.
- the acute lethal dose (LD 11 ) was the lowest concentration of the anticholinergic drug where 4 mice of 4 tested died within 5 minutes after an i.v. bolus dose.
- LDso-interval The LD 50 -interval was between the highest dose where 4 mice survived and the lowest dose where 4 mice died within 5 minutes after an i.v. bolus dose.
- the animal is slightly anaestetized by ether and an infusion cannula is inserted into a tail vein. While still asleep the rat is placed in a simple device, made of a coarse, somewhat elastic net fixing the rat in a constant position. Electrodes are attached to the extremities and connected to an ECG-pulse pre-amplifier and a Grass polygraph. By recording the ECG, the heart rate can then be determined.
- the substance is injected, i.v. in the infusion cannula and flushed with physiological saline.
- ECG is recorded 0.25, 0.5, 1, 2, 3 and 5 minutes after completed injection and then every 5 minutes until the original heart rate is obtained.
- the compound 1 according to the invention is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes.
- the magnesium stearate is then added, the resultant mixture being mixed for about 5 minutes and then compressed into tablet form with or without filmcoating.
- the compound 1 according to the invention is mixed with ingredients 2 and 3 and then milled.
- the resulting mixture is then mixed with ingredients 4 and 5 and then filled into capsules of appropriate size.
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- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT89850017T ATE65990T1 (de) | 1988-01-22 | 1989-01-20 | Amine, ihre verwendung und herstellung. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8800207 | 1988-01-22 | ||
SE8800207A SE8800207D0 (sv) | 1988-01-22 | 1988-01-22 | Nya aminer, deras anvendning och framstellning |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0325571A1 EP0325571A1 (en) | 1989-07-26 |
EP0325571B1 true EP0325571B1 (en) | 1991-08-07 |
Family
ID=20371146
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP89901611A Pending EP0354234A1 (en) | 1988-01-22 | 1989-01-20 | New amines, their use and preparation |
EP89850017A Expired - Lifetime EP0325571B1 (en) | 1988-01-22 | 1989-01-20 | New amines, their use and preparation |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP89901611A Pending EP0354234A1 (en) | 1988-01-22 | 1989-01-20 | New amines, their use and preparation |
Country Status (17)
Country | Link |
---|---|
EP (2) | EP0354234A1 (xx) |
JP (1) | JP2664503B2 (xx) |
AT (1) | ATE65990T1 (xx) |
AU (1) | AU635493B2 (xx) |
CA (1) | CA1340223C (xx) |
DE (2) | DE68900180D1 (xx) |
DK (1) | DK172103B1 (xx) |
ES (1) | ES2029384T4 (xx) |
FI (1) | FI109900B (xx) |
GR (1) | GR3002854T3 (xx) |
HK (1) | HK64494A (xx) |
HU (2) | HU212729B (xx) |
LU (1) | LU90259I2 (xx) |
NL (1) | NL980020I2 (xx) |
NO (2) | NO173496C (xx) |
SE (1) | SE8800207D0 (xx) |
WO (1) | WO1989006644A1 (xx) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100482635C (zh) * | 1997-03-27 | 2009-04-29 | 辉瑞健康公司 | 新颖化合物,其用途及制法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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EP1629834A1 (en) | 2004-08-27 | 2006-03-01 | KRKA, D.D., Novo Mesto | Sustained release pharmaceutical composition of tolterodine |
JP4513535B2 (ja) * | 2004-12-03 | 2010-07-28 | 住友化学株式会社 | トルテロジンの製造方法 |
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ITMI20060110A1 (it) * | 2006-01-24 | 2007-07-25 | Dipharma Spa | Procedimento per la purificazione di tolterodina |
MX2008011963A (es) | 2006-03-20 | 2008-10-01 | Pfizer Ltd | Derivados de amina. |
KR101488740B1 (ko) | 2006-06-12 | 2015-02-03 | 유씨비 파마 게엠베하 | 새로운 키랄 중간체, 그 키랄 중간체의 제조방법 및 톨테로딘, 페소테로딘 또는 그 활성대사물질의 제조에서 그키랄 중간체의 사용 |
EP2044001B1 (en) | 2006-06-20 | 2016-11-23 | LEK Pharmaceuticals d.d. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-n-alkyl-3-phenylpropylamines |
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CZ302585B6 (cs) * | 2007-02-26 | 2011-07-20 | Zentiva, A. S. | Krystalická sul 2-[(1R)-3-[bis(1-methylethyl)amino]-1-fenylpropyl]-4-methylfenolu s kyselinou (2R,3R)-2,3-dihydroxybutandiovou |
ITMI20082055A1 (it) * | 2008-11-19 | 2009-02-18 | Dipharma Francis Srl | Procedimento per la preparazione di (r)-tolterodina base libera |
KR20120014583A (ko) * | 2009-05-11 | 2012-02-17 | 라티오팜 게엠베하 | 타르타르산 염 형태의 데스페소테로딘 |
IL210279A0 (en) | 2009-12-25 | 2011-03-31 | Dexcel Pharma Technologies Ltd | Extended release compositions for high solubility, high permeability acdtive pharmaceutical ingredients |
EP2364966A1 (en) | 2010-03-09 | 2011-09-14 | LEK Pharmaceuticals d.d. | Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-3-phenylpropylamines, intermediates for making hydroxytolterodine |
CN102329244A (zh) * | 2010-07-13 | 2012-01-25 | 凯瑞斯德生化(苏州)有限公司 | 一种rs-托特罗定的制备方法及中间体化合物 |
ITMI20110410A1 (it) * | 2011-03-15 | 2012-09-16 | Cambrex Profarmaco Milano Srl | Procedimento per la preparazione di (r)-tolterodina l-tartrato di forma cristallina definita |
ITMI20121232A1 (it) | 2012-07-16 | 2014-01-17 | Cambrex Profarmaco Milano Srl | Procedimento per la preparazione di 2-(3-n,n-diisopropilamino-1-fenilpropil)-4-idrossimetil-fenolo e suoi derivati |
CN110372571B (zh) | 2018-04-12 | 2022-11-15 | 中国科学院大连化学物理研究所 | 一种2-(2,2-二芳基乙基)-环胺衍生物或盐及合成和应用与组合物 |
WO2022256480A1 (en) * | 2021-06-03 | 2022-12-08 | Conagen Inc. | Arylcoumarin synthesis with azeotropic removal of water |
Family Cites Families (3)
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DK111894A (xx) * | 1962-11-15 | |||
GB1169944A (en) * | 1966-08-25 | 1969-11-05 | Geistlich Soehne Ag | Novel 3,3-Diphenylpropylamines and processes for the preparation thereof |
GB1169945A (en) * | 1966-08-25 | 1969-11-05 | Geistlich Soehne Ag | Pharmaceutical Compositions containing Diphenylalkyl-amine Derivatives |
-
1988
- 1988-01-22 SE SE8800207A patent/SE8800207D0/xx unknown
-
1989
- 1989-01-20 AU AU29329/89A patent/AU635493B2/en not_active Expired
- 1989-01-20 HU HU891069A patent/HU212729B/hu unknown
- 1989-01-20 EP EP89901611A patent/EP0354234A1/en active Pending
- 1989-01-20 AT AT89850017T patent/ATE65990T1/de not_active IP Right Cessation
- 1989-01-20 ES ES89850017T patent/ES2029384T4/es not_active Expired - Lifetime
- 1989-01-20 EP EP89850017A patent/EP0325571B1/en not_active Expired - Lifetime
- 1989-01-20 JP JP1501413A patent/JP2664503B2/ja not_active Expired - Lifetime
- 1989-01-20 CA CA000588821A patent/CA1340223C/en not_active Expired - Lifetime
- 1989-01-20 WO PCT/SE1989/000016 patent/WO1989006644A1/en active IP Right Grant
- 1989-01-20 DE DE8989850017T patent/DE68900180D1/de not_active Expired - Lifetime
- 1989-01-20 DE DE1998175024 patent/DE19875024I2/de active Active
-
1990
- 1990-07-11 NO NO903085A patent/NO173496C/no not_active IP Right Cessation
- 1990-07-19 DK DK172590A patent/DK172103B1/da not_active IP Right Cessation
- 1990-07-20 FI FI903688A patent/FI109900B/fi not_active IP Right Cessation
-
1991
- 1991-10-08 GR GR91401499T patent/GR3002854T3/el unknown
-
1994
- 1994-07-07 HK HK64494A patent/HK64494A/xx not_active IP Right Cessation
- 1994-12-15 HU HU94P/P00053P patent/HU210603A9/hu unknown
-
1998
- 1998-06-19 NL NL980020C patent/NL980020I2/nl unknown
- 1998-07-03 LU LU90259C patent/LU90259I2/fr unknown
- 1998-10-20 NO NO1998023C patent/NO1998023I1/no unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100482635C (zh) * | 1997-03-27 | 2009-04-29 | 辉瑞健康公司 | 新颖化合物,其用途及制法 |
Also Published As
Publication number | Publication date |
---|---|
WO1989006644A1 (en) | 1989-07-27 |
EP0325571A1 (en) | 1989-07-26 |
LU90259I2 (fr) | 1998-09-16 |
DE68900180D1 (de) | 1991-09-12 |
HU891069D0 (en) | 1991-11-28 |
AU635493B2 (en) | 1993-03-25 |
JP2664503B2 (ja) | 1997-10-15 |
GR3002854T3 (en) | 1993-01-25 |
HK64494A (en) | 1994-07-15 |
NO173496B (no) | 1993-09-13 |
NL980020I1 (nl) | 1998-09-01 |
HU210603A9 (en) | 1995-05-29 |
EP0354234A1 (en) | 1990-02-14 |
ES2029384T4 (es) | 2011-05-30 |
DK172590D0 (da) | 1990-07-19 |
HU212729B (en) | 1996-10-28 |
CA1340223C (en) | 1998-12-15 |
NO903085D0 (no) | 1990-07-11 |
ATE65990T1 (de) | 1991-08-15 |
NO173496C (no) | 1993-12-22 |
ES2029384T3 (es) | 1992-08-01 |
NO1998023I1 (no) | 1998-10-20 |
FI109900B (fi) | 2002-10-31 |
DE19875024I2 (de) | 2002-09-26 |
AU2932989A (en) | 1989-08-11 |
FI903688A0 (fi) | 1990-07-20 |
DK172590A (da) | 1990-07-19 |
HUT58040A (en) | 1992-01-28 |
DK172103B1 (da) | 1997-10-27 |
NO903085L (no) | 1990-07-11 |
NL980020I2 (nl) | 1999-02-01 |
JPH03503163A (ja) | 1991-07-18 |
SE8800207D0 (sv) | 1988-01-22 |
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